Osteoarthritis (OA) is the most common form of arthritis and the major cause of activity limitation and physical disability in older people. In the absence of disease modifying therapy, there is an urgent need for effective, widely available approaches to aid in the prevention and management of this common condition. Dietary factors associated with inflammation, obesity and other metabolic risk factors appear to play a role in OA pathogenesis. However, few human studies have studied the association between dietary factors and risk of future knee OA development. We have preliminary data from the Osteoarthritis Initiative (OAI), a large cohort with repeated measures of OA symptoms and radiographic outcomes, demonstrating that the Western dietary pattern, characterized by high intakes of red/ processed meats, refined grains, desserts / sweets, was associated with increased risk of radiographic knee OA. In contrast, the Prudent dietary pattern characterized by high intakes of fruits/ vegetables, legumes, whole grains, poultry, and fish was associated with reduced risk of knee OA. Hence, adherence to a healthy diet may provide a potential strategy for the prevention of knee OA. However, self-report dietary assessment methods, such as food-frequency questionnaires (FFQs) and diet records, may be subject to recall bias and measurement error. Biomarkers of dietary intake taking into account the nutrient bioavailability and metabolism may better represent a long-term nutritional status. Recently, metabolomics, by measuring a large number of downstream components or metabolic products (metabolites), provides the most integrated profile of biological status reflecting environmental, dietary and genetic interactions, and therefore may more precisely define dietary exposures and provide better estimates of disease risk in epidemiologic studies. To date, intervention studies have identified a variety of metabolites related to the dietary intake of major foods. More than 50 of them have been validated by multiple studies. To date, no study has ever assessed the association between metabolites of dietary intake and future risk of knee OA. We propose a nested case-control study in OAI cohort including 261 incident knee OA cases and 261 matched controls to examine whether individual metabolites and metabolomic profiles of dietary intake predict subsequent risk of development of knee OA, and whether diet-related metabolites and metabolomic profiles influence imaging biomarkers of knee OA. Finally, we will examine whether imaging biomarkers of knee OA mediate the associations of diet-related metabolomic profiles with risk of knee OA. This study will help to identify dietary factors associated with knee OA development, and offer the potential for effective OA prevention strategies; therefore, it may have large public health and clinical implications.